Oral administration is one of the most convenient ways of delivering drugs, but therapeutic proteins often must be administered by an invasive method, such as intravenous or subcutaneous injection (Morishita et al., 2006, Drug Discov Today 11:905-10). Oral delivery of protein drugs is not generally feasible due to poor stability during passage through the gastrointestinal tract and low permeability across the intestinal wall, resulting in insufficient bioavailability. To increase oral bioavailability of proteins, various encapsulation strategies have been developed to protect the polypeptides from enzymatic digestion (Muller G., 2010, Curr Issues Mol Biol 13(1):13-24), but most have encountered roadblocks that prevent them from advancing to a clinical setting (Khafagy et al., 2007, Adv Drug Deliv Rev 59(15):1521-46).
L. lactis is a gram-positive bacterium widely used in the food industry for production of fermented products such as buttermilk and cheese and is therefore routinely consumed in these foods. L. lactis has a safe association with humans and has been proposed for use as a probiotic (Balcazar et al., 2007, Br J Nutr 97(3):522-7). There has been increasing interest in the use of L. lactis as a mucosal delivery vehicle because it can survive passage through the stomach acid and contact with bile (Klijn et al., 1995, Appl Environ Microbiol 61(7):2771-4) and it can be engineered to express and secrete targeting molecules and adjuvants (Nouaille et al., 2003, Genet Mol Res 2(1):102-11). Antigens and DNA have been introduced for mucosal vaccine delivery, single-chain variable fragments (scFvs) for anti-infectives, and allergens for allergy prevention (Wells et al., 2008, Nat Rev Microbiol 6(5):349-62). To address potential safety concerns of using live L. lactis in humans, the thymidylate synthase gene can be removed from the host genome, rendering the auxotrophic bacteria dependent on thymidine or thymine for survival and thus biologically contained (Steidler et al., 2003, Nat Biotechnol 21(7):785-9). In addition, since the recombinant protein is still locally produced when the bacteria reach the intestine, proteolytic degradation is attenuated. A study involving the use of interleukin-10-secreting L. lactis to treat Crohn's disease has passed phase I clinical trials, supporting the notion that this live microorganism is a viable platform for oral protein delivery (Braat et al., 2006, Clin Gastroenterol Hepatol 4(6):754-9; Steidler et al., 2000, Science 289 (5483): 1352-5).
Oral administration of a number of classes of agents is limited by poor absorption, degradation by gastric and intestinal enzymes or instability of the agent in aqueous solutions generally and in the low pH environment of the stomach in particular. This is especially problematic for delivery of protein or peptide bioactive agents, which at present are primarily administered parenterally. However, other types of bioactive agents may exhibit similar problems when orally administered.
Oral delivery of insulin to diabetic patients is highly desirable because it would be noninvasive and more closely mimic normal physiology, but this route of administration typically results in low bioavailability due to low pH, enzymatic degradation along the gastrointestinal tract, and poor absorption. Thus, there is a need in field to develop improved oral delivery systems having a desirable bioavailability outcome. The present invention satisfies this need.